Biodegradable polyacetal polymers and methods for their formation and use

ABSTRACT

The present invention relates to biodegradable biocompatible polyacetals, methods for their preparation, and methods for treating mammals by administration of biodegradable biocompatible polyacetals. A method for forming the biodegradable biocompatible polyacetals combines a glycol-specific oxidizing agent with a polysaccharide to form an aldehyde intermediate which is combined with a reducing agent to form the biodegradable biocompatible polyacetal. The resultant biodegradable biocompatible polyacetals can be chemically modified to incorporate additional hydrophilic moieties. A method for treating mammals includes the administration of the biodegradable biocompatible polyacetal in which biologically active compounds or diagnostic labels can be disposed.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 08/871,528, filed Jun.9, 1997, now U.S. Pat. No. 5,863,990, which is a divisional of U.S. Ser.No. 08/421,766, filed Apr. 14, 1995, now U.S. Pat. No. 5,811,510, theentire teachings of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Polymers which are degraded by a physical or chemical process inresponse to contact with body fluid, while implanted or injected, aregenerally considered to be biodegradable. Biodegradable polymers havebeen the subject of increasing interest as materials which can beemployed to form a wide variety of pharmaceutical preparations and otherbiomedical products. Examples of medical applications for biodegradablepolymers include tablet coatings, plasma substitutes, gels, contactlenses, surgical implants, systems for controlled drug release, asingredients of eyedrops, and as long circulating and targeted drugs.

Many polymers have hydrophobic domains and, consequently, theirbiocompatability is limited. Hydrophobic polymers are vulnerable tonon-specific interactions with proteins and lipids which also may causeundesirable side effects. In addition, synthetic polymers, such asvinyl, acrylic and methacrylic polymers, which typically have ahydrophobic main chain that do not degrade readily in vivo.

Hydrophilic polymers are common in nature. For example, polysaccharidesare naturally-occurring polymers which include hydrolytically-sensitiveacetals in their main chain. However, polysaccharides can interact withcell receptors and/or plasma opsonins, which can cause adverse reactionsand other non-desirable effects.

Polyacetals can be formed synthetically. However, most syntheticpolyacetals contain acetal group not in the main chain. Further, knownsynthetic polyacetals with acetal groups in the main chain areessentially hydrophobic and have limited solubility in water. They alsodo not include pharmaceutical substituents.

Therefore, a need exists for a polymer which overcomes or minimizes theabove-referenced problems.

SUMMARY OF THE INVENTION

The present invention relates to biodegradable polyacetals, methods fortheir preparation, and methods for treating and studying mammals byadministration of biodegradable polyacetals.

Biodegradable biocompatible polyacetals of the present invention havethe following chemical structure: ##STR1## R¹ is a biocompatible groupand includes a carbon atom covalently attached to C¹. R^(x) includes acarbon atom covalently attached to C². "n" is an integer. R², R³, R⁴ andR⁵ are biocompatible groups and are selected from the group consistingof hydrogen and organic moieties. At least one of R¹, R², R³, R⁴ and R⁵is hydrophilic.

One method for forming a biodegradable polyacetal of the inventionincludes combining a molar excess of a glycol-specific oxidizing agentwith a polysaccharide to form an aldehyde intermediate. The aldehydeintermediate is then reacted to form the biodegradable polyacetal.

A second method for forming biodegradable polyacetals includes combininga cationic initiator with a reactant having the chemical structure:##STR2## The reactant is converted to a polymer having the chemicalstructure: ##STR3## P¹ is a protected hydrophilic group which includes acarbon atom covalently attached to C¹. P^(x) is a protected hydrophilicgroup which includes a carbon atom covalently attached to C². "n" is aninteger. At least one of P¹, P², P³, P⁴ and P⁵ is selected from hydrogenand protected hydrophilic groups.

The method for treating a mammal comprises administering thebiodegradable biocompatible polyacetal to the mammal. Pharmaceuticalexcipients, such as biologically active compounds or diagnostic labels,can be incorporated into a solution or a gel which includes thebiodegradable biocompatible polyacetal of the invention. Mixtures ofpharmaceutical excipients can be disposed within the solution or gel.For example, pharmaceutical excipients can be linked to the polyacetalby a chemical bond or dispersed throughout the biocompatiblebiodegradable polyacetal solution or gel.

This invention has many advantages. For example, the reactants employedto form the biodegradable biocompatible polyacetals are readilyavailable. Further, the resultant biodegradable biocompatiblepolyacetals can be modified to obtain products with desirableproperties, such as by modification with additional hydrophilicmoieties, biologically active groups, or diagnostic groups. Also, thebiodegradable biocompatible polyacetal can incorporate pharmaceuticalexcipients. The biodegradable biocompatible polyacetals can be formed tomeet narrow requirements of biodegradability and hydrophilicity. Thebiodegradable biocompatible polyacetals of the present invention aredistinct from naturally-occurring polysaccharides. For example, thepolysaccharide ring structure is cleaved during the synthesis of thebiodegradable biocompatible polyacetals and is essentially absent fromthe polymer structure. Further, the biodegradable biocompatiblepolyacetals of the present invention have a higher degree ofbiocompatability relative to the polysaccharides from which they arederived, since they generally do not contain cyclic carbohydrates whichare potentially receptor recognizable.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a ¹³ C NMR spectrum of a biodegradable biocompatiblepolyacetal of the present invention.

FIG. 2 is a plot of the distribution of a radiolabelled biodegradablebiocompatible polyacetal of the invention twenty hours after injectionof the polyacetal into Sprague-Dawley CD rats.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention, either as steps of theinvention or as combination of parts of the invention, will now be moreparticularly described and pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprinciple features of the invention may be employed in variousembodiments without departing from the scope of the invention.

The biodegradable biocompatible polyacetals of the present invention arehydrophilic, hydrolyzable, contain acetal groups in the main chain andcan be functionalized. Solubility of biodegradable biocompatiblepolyacetals can be modified by subsequent substitution of additionalhydrophilic or hydrophobic groups. Biodegradable biocompatiblepolyacetals of the present invention can be employed as components ofbiomaterials, pharmaceutical formulations, medical devices, implants,and can be combined with biologically active compounds and diagnosticlabels.

"Biodegradable," as that term is used herein, means polymers which aredegraded in response to contact with body fluid while implanted orinjected in vivo. Examples of biodegradation processes includehydrolysis, enzymatic action, oxidation and reduction. Suitableconditions for hydrolysis, for example, include exposure of thebiodegradable polyacetals to water at a temperature and a pH ofcirculating blood. Biodegradation of polyacetals of the presentinvention can be enhanced in low pH regions of the mammalian body, e.g.an inflamed area.

"Biocompatible," as that term is used herein, means exhibition ofessentially no cytotoxicity while in contact with body fluids."Biocompatibility" also includes essentially no interactions withrecognition proteins, e.g., naturally occurring antibodies, cellproteins, cells and other components of biological systems. However,substances and functional groups specifically intended to cause theabove effects, e.g., drugs and prodrugs, are considered to bebiocompatible.

The biodegradable biocompatible polyacetals of the present inventionhave the following chemical structure: ##STR4## R¹ is biocompatible andincludes a carbon atom covalently attached to C¹. R^(x) includes acarbon atom covalently attached to C². "n" is an integer. R², R³, R⁴ andR⁵ are biocompatible and are selected from the group consisting ofhydrogen and organic moieties. At least one of R¹, R², R³, R⁴ and R⁵ ishydrophilic. Examples of suitable organic moieties are aliphatic groupshaving a chain of atoms in a range of between about one and twelveatoms.

The term "hydrophilic" as it relates to R¹, R², R³, R⁴ and R⁵ denotesorganic moieties which contain ionizable, polar, or polarizable atoms,or which otherwise may bind water molecules. Examples of particularhydrophilic organic moieties which are suitable include carbamates,amides, hydroxyls, carboxylic acids and their salts, carboxylic acidesters, amines, sulfonic acids and their salts, sulfonic acid esters,phosphoric acids and their salts, phosphate esters, polyglycol ethers,polyamines, polycarboxylates, polyesters, polythioethers, etc. Inpreferred embodiments of the present invention, at least one of R¹, R²,R³, R⁴ and R⁵ include a carboxyl group (COOH), an aldehyde group (CHO)or a methylol (CH₂ OH). In another preferred embodiment of the presentinvention, R¹, R², R³, R⁴ and R⁵ are methylols. In still anotherpreferred embodiment of the present invention, R¹ and R² are methylolsand R³, R⁴, and R⁵ are hydrogens.

In yet another embodiment of the present invention, at least one of R¹,R², R³, R⁴ or R⁵ is a nitrogen-containing compound. Thenitrogen-containing compound can be a drug or a crosslinking agent or afunctional group which is suitable as a modifier of biodegradablebiocompatible polyacetal behavior in vivo. Examples of such functionalgroups include antibodies, their fragments, receptor ligands and othercompounds that selectively interact with biological systems.

Alternatively, the nitrogen-containing compound can have a chemicalstructure of --C_(n) H_(2n) NR⁶ R⁷, wherein "n" is an integer. In oneembodiment, "n" is one. R⁶ and R⁷ can include hydrogen, organic orinorganic substituents. Examples of suitable organic or inorganic groupsinclude aliphatic groups, aromatic groups, complexes of heavy metals,etc.

The biodegradable biocompatible polyacetals of the invention can becrosslinked. A suitable crosslinking agent has the formula X¹ --(R)--X²,where R is a spacer group and X¹ and X² are reactive groups. Examples ofsuitable spacer groups include biodegradable or nonbiodegradable groups,for example, aliphatic groups, carbon chains containing biodegradableinserts such as disulfides, esters, etc. The term "reactive group," asit relates to X¹ and X², means functional groups which can be connectedby a reaction within the biodegradable biocompatible polyacetals,thereby crosslinking the biodegradable biocompatible polyacetals.Suitable reactive groups which form crosslinked networks with thebiodegradable biocompatible polyacetals include epoxides, halides,tosylates, mesylates, carboxylates, aziridines, cyclopropanes, esters,N-oxysuccinimde esters, disulfides, anhydrides etc.

In one of the preferred embodiments of the present invention, thebiodegradable biocompatible polyacetals are crosslinked withepibromohydrin or epichlorohydrin. More preferably, the epibromohydrinor epichlorohydrin is present in an amount in the range of between aboutone and twenty five percent by weight of the crosslinked biodegradablebiocompatible polyacetals.

Alternatively, the term "reactive" group as it relates to X¹ and x²means a nucleophilic group that can be reacted with an aldehydeintermediate of the biodegradable biocompatible polyacetals, therebycrosslinking the biodegradable biocompatible polyacetals. Suitablereactive groups for the aldehyde intermediate include amines, thiols,polyols, alcohols, ketones, aldehydes, diazocompounds, boronderivatives, ylides, isonitriles, hydrazines and their derivatives andhydroxylamines and their derivatives, etc.

In one embodiment, the biodegradable biocompatible polyacetals of thepresent invention have a molecular weight of between about 0.5 and 500kDa. In a preferred embodiment of the present invention, thebiodegradable biocompatible polyacetals have a molecular weight ofbetween about 1 and 100 kDa.

At least one of R¹, R², R³, R⁴ and R⁵ can comprise a biologically-activecompound, such as a drug molecule. Examples of suitable drug moleculescomprise a biologically active functional group fragment or moiety, or adiagnostic label. Specific examples of suitable drug molecules includeantibiotics, analgesics, amino acids, vitamins, and chemotherapeuticagents. Examples of biologically active compounds are chemotherapeuticagents, antibacterial agents, antiviral agents, immunomodulators,hormones and their analogs, enzymes, inhibitors, alkaloids, therapeuticradionuclides, etc. Suitable chemotherapeutic compounds are, forexample, alkylating agents, anthracyclines, doxorubicin, cisplatin,carboplatin, vincristine, mitromycine, dactinomycines, etc. Othersuitable compounds include therapeutic radionuclides, such as β-emittingisotopes of rhenium, cesium, iodine, and alkaloids, etc. In oneembodiment of the present invention, at least one of R¹, R², R³, R⁴ andR⁵ contains doxorubicin.

In another embodiment of the present invention, at least one of R¹, R²,R³, R⁴ and R⁵ comprises a diagnostic label. Examples of suitablediagnostic labels include diagnostic radiopharmaceuticals, contrastagents for magnetic resonance imaging, contrast agents for computedtomography and other methods of X-ray imaging and agents for ultrasounddiagnostic methods, etc. Diagnostic radiopharmaceuticals includeγ-emitting radionuclides, e.g., indium-111, technetium-99m andiodine-131, etc. Contrast agents for MRI (Magnetic Resonance Imaging)include magnetic compounds, e.g. paramagnetic ions, iron, manganese,gadolinium, lanthanides, organic paramagnetic moieties andsuperparamagnetic compounds, e.g., iron oxide colloids, ferritecolloids, etc. Contrast agents for computed tomography and other X-raybased imaging methods include compounds absorbing X-rays, e.g., iodine,barium, etc. Contrast agents for ultrasound based methods includecompounds which can absorb, reflect and scatter ultrasound waves, e.g.,emulsions, crystals, gas bubbles, etc. Still other examples includesubstances useful for neutron activation, such as boron. Further,substituents can be employed which can reflect, scatter, or otherwiseaffect X-rays, ultrasound, radiowaves, microwaves and other rays usefulin diagnostic procedures. In a preferred embodiment, at least one of R¹,R² and R³ comprises a paramagnetic ion or group.

Optionally, the invention can be a composition in the form of a gel ofthe biodegradable biocompatible acetal and a biologically activecompound disposed within the gel. Alternatively or additionally, adiagnostic label can be disposed within the gel.

In another embodiment, the invention can be a composition in the form ofa solution of the biodegradable biocompatible acetal and a biologicallyactive compound dissolved within the solution. Alternatively, adiagnostic label can be dissolved within the solution.

In one embodiment of the method for forming the biodegradablebiocompatible polyacetal of the present invention, a suitablepolysaccharide is combined with a molar excess of a glycol-specificoxidizing agent to form an aldehyde intermediate. A "molar excess of aglycol-specific oxidizing agent," as that phrase is employed herein,means an amount of the glycol-specific oxidizing agent that providesoxidative opening of essentially all carbohydrate rings of thepolysaccharide. The aldehyde intermediate is then combined with areducing agent to form the biodegradable biocompatible polyacetal. Thebiodegradable biocompatible polyacetals of the present invention canform linear or branched structures. The biodegradable biocompatiblepolyacetal of the present invention can be optically active. Optionally,the biodegradable biocompatible polyacetal of the present invention canbe racemic.

Structure, yield and molecular weight of the resultant polyaldehydedepend on the initial polysaccharide. Polysaccharides that do notundergo significant depolymerization in the presence of glycol-specificoxidizing agents, for example, poly (1→6) hexoses, are preferable.Examples of suitable polysaccharides include starch, cellulose, dextran,etc. A particularly preferred polysaccharide is dextran. Examples ofsuitable glycol-specific oxidizing agents include sodium periodate, leadtetra-acetate, etc. Examples of suitable reducing agents include sodiumborohydride, sodium cyanoborohydride, etc.

In an embodiment wherein dextran is employed as a reactant to form thebiodegradable biocompatible polyacetal, the glycol-specific oxidationcan be conducted at a temperature between about 25° C. and 40° C. for aperiod of about eight hours at a suitable pH. Temperature, pH andreaction duration can affect the reaction rate and polymer hydrolysisrate. The reaction is preferably conducted in the absence of light. Oneskilled in the art can optimize the reaction conditions to obtainpolymers of desired composition. The resultant aldehyde intermediate canbe isolated and combined with a solution of a reducing agent for aperiod of about two hours to form the biodegradable biocompatiblepolyacetal after isolation. Alternatively, aldehyde groups can beconjugated with a variety of compounds or converted to other types offunctional groups.

It is believed that the carbohydrate rings of a suitable polysaccharidecan be oxidized by glycol-specific reagents with cleavage of carbonbonds between carbon atoms that are connected to hydroxyl groups. Thefollowing mechanism is an example of what is believed to occur. ##STR5##This process can be complicated by the formation of intra andinterpolymer hemiacetals which can inhibit further polysaccharideoxidation. However, oxidative opening of the polysaccharide rings can becontrolled by controlling the reaction conditions. In the presentinvention, it can be demonstrated that the polysaccharide oxidation,followed by reduction, causes synthesis of macromolecular biodegradablebiocompatible polyacetals. The structure of the biodegradablebiocompatible polyacetal obtained by the above mentioned method isdependent upon the precursor polysaccharide. Although it is generallynot desirable, the polyacetal can contain intermittent irregularitiesthroughout the polyacetal, such as incompletely oxidized additionalgroups or moieties in the main chain or in the side chains, as shownbelow: ##STR6## wherein k, m, and n are integers greater than or equalto one.

Since it is believed that oxidation does not affect configurations atthe C¹ and C² positions, the aldehyde intermediate and the polyacetalretain the configuration of the parent polysaccharide and are formed instereoregular isotactic forms.

The resultant biodegradable biocompatible polyacetal can be chemicallymodified by, for example, crosslinking the polyacetals to form a gel.The crosslink density of the biodegradable biocompatible polyacetal isgenerally determined by the number of reactive groups in the polyacetaland by the number of crosslinking molecules, and can be controlled byvarying the ratio of polyacetal to the amount of crosslinker present.

For example, the biodegradable biocompatible polyacetal can be combinedwith a suitable aqueous base, such as sodium hydroxide, and crosslinkedwith epibromohydrin. Control of the amounts of epibromohydrin candetermine the degree of crosslinking within the biodegradablebiocompatible polyacetal gel. For example, biodegradable biocompatiblepolyacetals can be exposed to varying amounts of epibromohydrin for aperiod of about eight hours at a temperature about 80° C. to formcrosslinked biodegradable biocompatible polyacetal gels which vary incrosslink density in relation to the amount of epibromohydrin utilized.The crosslinked biodegradable biocompatible polyacetal gel can furtherbe reacted with a drug.

Treatment of the biodegradable biocompatible polyacetal with a suitablebase, such as triethylamine in dimethylsulfoxide (DMSO), and ananhydride provides, for example, a derivatized polyacetal solution.Control of the amount of anhydride within the biodegradablebiocompatible polyacetal can determine the degree of derivitization ofthe polyacetal in the solution.

In another embodiment of the present invention, treatment of poly-lysinelabeled with DPTA (diethylenetriaminepentaacetic acid) with thebiodegradable biocompatible polyacetal aldehyde, in water, for example,followed by subsequent reduction in water, provides a derivatizedpolyacetal solution.

In yet another embodiment of the present invention, oxidation of adextran-stabilized iron oxide colloid with sodium periodate in water,followed by reduction with sodium borohydride in water, also forms aderivatized biodegradable biocompatible polyacetal solution.

Polyacetals of this invention can have a variety of functional groups.For example, aldehyde groups of an intermediate product ofpolysaccharide oxidation can be converted not only into alcohol groups,but also into amines, thioacetals, carboxylic acids, amides, esters,thioesters, etc.

Terminal groups of the polymers of this invention can differ from R¹,R², R³, R⁴, and R⁵. Terminal groups can be created, for example, byselective modification of each reducing and non-reducing terminal unitof the precursor polysaccharide. One skilled in the art can utilizeknown chemical reactions to obtain desired products with varyingterminal groups. For example, a hemiacetal group at the reduced end ofthe polyacetal can be readily and selectively transformed into acarboxylic acid group and further into a variety of other functionalgroups. A primary alcohol group at the non-reduced end can beselectively transformed into an aldehyde group and further into avariety of functional groups.

Alternatively, the biodegradable biocompatible polyacetals of thepresent invention can be formed by combining a cationic initiator with aprecursor compound having the chemical structure: ##STR7## which forms apolymer having the chemical structure: ##STR8## P¹ is a protectedhydrophilic group which includes a carbon atom covalently attached toC¹. P^(x) includes a carbon atom covalently attached to C². "n" is aninteger. At least one of P¹, P², P³, P⁴ and P⁵ is selected from hydrogenand protected hydrophilic groups suitable for conversion. P¹, P², P³, P⁴and P⁵ do not interfere with the cationic polymerization. Furthermore,P¹, P², P³, P⁴, and P⁵ are suitable for conversion to hydrophilic groupsas described above.

"Protected hydrophilic group," as that term is used herein, means achemical group which will not interfere with decyclization of theprecursor compound by the cationic initiator or subsequentpolymerization, and which, upon additional treatment by a suitableagent, can be converted to a hydrophilic functional group. Examples ofprotected hydrophilic groups include esters, ethers, thioesters,thioethers, vinyl groups, haloalkyl groups, etc.

A method of treating mammals comprises administering to the mammal thebiodegradable biocompatible polyacetal of this invention. For example,polyacetal can be administered in the form of soluble linear polymers,copolymers, colloids, particles, gels, solid items, fibers, films, etc.Biodegradable biocompatible polyacetals of this invention can be used asdrug carriers and drug carrier components, in systems of controlled drugrelease, preparations for low-invasive surgical procedures, etc.Pharmaceutical formulations can be injectable, implantable, etc.

In one embodiment, a method for treating a mammal comprisesadministering to the mammal the biodegradable biocompatible polyacetalof the invention as a packing for a surgical wound from which a tumor orgrowth has been removed. The biodegradable biocompatible polyacetalpacking will replace the tumor site during recovery and degrade anddissipate as the wound heals.

In another example, pharmaceutical excipients are incorporated in thebiodegradable biocompatible polyacetal to form a biodegradablebiocompatible mass of polyacetal in which the pharmaceutical excipientis entrapped. This can be achieved, e.g., by coupling the polyacetalwith a pharmaceutical excipient. Alternatively, the pharmaceuticalexcipient can be entrapped by dissolution of the pharmaceuticalexcipient in the presence of the biodegradable biocompatible polyacetalduring removal of a solvent. When these masses are implanted into amammal, slow hydrolysis of the biodegradable biocompatible polyacetalmass occurs with continuous slow release of the excipient in the mammalat the location where its function is required.

The biodegradable biocompatible polyacetals of the present invention canbe monitored in vivo by suitable diagnostic procedures. The diagnosticprocedure can detect, for example, polyacetal disposition (e.g.,distribution, localization, density, etc.) or the release of drugs,prodrugs, biologically active compounds or diagnostic labels from thebiodegradable biocompatible polyacetals over a period of time. Suchdiagnostic procedures include nuclear magnetic resonance imaging (NMR),magnetic resonance imaging (MRI), ultrasound, radio waves, microwaves,X-ray, scintillography, positron emission tomography (PET), etc.

In one embodiment of the present invention, the biodegradablebiocompatible polyacetal can be used as an interface component. The term"interface component" as used herein, means a component, such as acoating, of an object whereby adverse, or cytotoxic reactions, to theobject are substantially prevented by the component. It should beunderstood that said object can be microscopic or macroscopic. Examplesof microscopic objects include macromolecules, colloids, vesicles,liposomes, emulsions, gas bubbles, nanocrystals, etc. Examples ofmacroscopic objects include surfaces, such as surfaces of surgicalequipment, test tubes, perfusion tubes, items contacting biologicaltissues, etc. It is believed that interface components can, for example,provide the object protection from direct interactions with cells andopsonins and, thus, to decrease the interactions of the object with thebiological system.

Surfaces can be modified by the biodegradable biocompatible polyacetalsof the present invention by, for example, conjugating functional groupsof the biodegradable biocompatible polyacetals with functional groupspresent on the surface to be modified. For example, aldehyde groups ofthe biodegradable biocompatible polyacetal precursors can be linked withamino groups by employing reducing agents or isocyanides. Alternatively,carboxyl groups of the biodegradable biocompatible polyacetals can beconjugated with amino, hydroxy, sulphur-containing groups, etc. Inanother embodiment, a biodegradable biocompatible polyacetal of theinvention which includes a suitable terminal group can be synthesized,such as a polyalcohol having a terminal carboxylic group. A polymer canbe connected to a surface by reaction of the terminal group. Examples ofsuitable polymers include those formed, for example, by oxidation of areducing-end acetal group into a carboxyl group, such as by using iodineor bromine. The remainder of the polysaccharide is then oxidized byemploying a molar excess of a glycol-specific oxidizing agent to form analdehyde. The aldehydes can be selectively modified by, for example,reduction into hydroxyl groups. The resulting polymer will generallyhave one terminal carboxyl group that can be used for one-pointmodification, such as by employing a carbodiimide.

In still another embodiment, a polysaccharide can be linked with asurface by reaction of a reducing-end aldehyde group of thepolysaccharide, and subsequent oxidation and further conversion of theremainder of the polysaccharide.

It is to be understood that the biodegradable biocompatible polyacetalsof this invention can be conjugated with macromolecules, such asenzymes, polypeptides, proteins, etc., by the methods described abovefor conjugating the biodegradable biocompatible polyacetals withfunctional groups present on a surface.

The biodegradable biocompatible polyacetals of the invention can also beconjugated with a compound that can physically attach to a surface via,for example, hydrophobic, van der Waals, and electrostatic interactions.For example, the biodegradable biocompatible polyacetal precusors can beconjugated with lipids, polyelectrolytes, proteins, antibodies, lectins,etc.

It is believed that interface components can prolong circulation ofmacromolecular and colloidal drug carriers. Therefore, biologicallyactive compounds, diagnostic labels, etc., being incorporated in suchcarriers, can circulate throughout the body without stimulating animmunogenic response and without significant interactions with cellreceptors and recognition proteins (opsonins). Further, interfacecomponents can be used to modify surfaces of implants, catheters, etc.In other embodiments of the present invention, biomedical preparationsof the biodegradable biocompatible polyacetal can be made in variousforms. Examples include implants, fibers, films, etc.

The invention will now be further and specifically described by thefollowing examples. All parts and percentages are by weight unlessotherwise stated.

EXEMPLIFICATION EXAMPLE 1 Formation of Aldehyde-Containing Polymer byPolysaccharide Oxidation

Dextran (MW=485 kDa), 22.5 g was dissolved in 500 mL water. Sodiumperiodate, 57 g, was dissolved in 200 mL of water and mixed with thedextran solution at 25° C. After 8 hours of incubation, thehigh-molecular components were extracted from the reaction mixture byflow dialysis, using a hollow fiber Amicon™ cartridge with a 10 kDacutoff. The reaction mixture was concentrated to 200 mL, then a 10 foldvolume of water (2 liters) was passed through. A forty mL aliquot of thereaction mixture was lyophilized to yield 1.81 g of product. Theresultant polymer was slowly soluble in water at neutral and low pH andreadily dissolved at pH>7 and remained soluble after pH adjustment topH<7. Ten milligrams of the polymer were dissolved in deuterium oxideand a proton NMR was obtained.

EXAMPLE 2 Formation of Polyalcohol by Reduction of Aldehyde-ContainingPolymer

Sodium borohydride, 20 g, was dissolved in 20 mL water and mixed with160 mL of 4.5% solution of the aldehyde containing polymer fromExample 1. After 2 hours of incubation, the pH was adjusted to 6. Twentyminutes later, high molecular components were extracted by flow dialysis(as described in Example 1) and separated into two fractions using anAmicon™ cartridge with a 100 kDa cutoff. Both fractions werelyophilized. Yields: low molecular weight fractions: 2.4 g; highmolecular weight fraction: 3.1 g. Ten milligrams of low molecular weightpolymer were dissolved in 1 mL of deutero DMSO and proton NMR wereobtained. FIG. 1 is a ¹³ C NMR of the polyacetal, dissolved in deuteriumoxide, which demonstrates carbons functionalized by alcoholfunctionality in the biodegradable biocompatible polyacetal.

EXAMPLE 3 Formation of Crosslinked Polyalcohol Gels

760 milligrams of a high molecular weight fraction of polyalcoholpolymer formed in Example 2 was dissolved in 10 mL of 5 N sodiumhydroxide. Eight mL of the solution was divided into equal portions into4 test tubes, 2 mL in each. Epibromohydrin was added into each test tubein varying amounts: 20 microliters (tube #1), 50 microliters (tube #2),100 microliters (tube #3), and 200 microliters (tube #4). The mixtureswere carefully stirred to emulsify epibromohydrin with the polyalcohol.The reaction mixtures were incubated at 80° C. for 8 hours. After theincubation, gels were pulled out of the test tubes and washed indeionized water overnight.

The resultant gels differed in swelling volumes and rigidity. Gelsswelled in proportion to the amount of bifunctional reagent used; i.e.gel #1 swelled approximately 10 fold whereas gel #4 did not swell.Rigidity of the gels increased with the increased amounts ofbifunctional reagent. After initial swelling, volumes of the gels didnot change over a 7 day period.

EXAMPLE 4 Degradability of Crosslinked Polyalcohol Gels

Gels #1 (1 mL) and #3 (0.5 mL) of Example 3 were placed into 20 mL of0.01 M HCl and incubated at 25° C. under slow stirring. By the thirdhour of incubation, gel #1 was completely dissolved. Gel #3 wascompletely dissolved by day 4.

EXAMPLE 5 Crosslinked Activated Gel

Ten milligrams of high molecular weight fraction polyalcohol fromExample 2 was disclosed. Epibromohydrin, 50 microliters, was added andthe mixture was stirred to emulsify epibromohydrin. The reaction mixturewas incubated in a test tube at 60° C. for 1 hour. After the incubation,the gel was extracted from the test tube and washed in deionized waterfor 3 hours.

The gel was transferred into 2 mL of doxorubicine hydrochloridesolution, 0.2 milligrams/mL, and the pH was adjusted to 8.5. After 14hours of incubation, the gel was washed in water and then incubated in0.001 M HCl for 3 hours (pH adjusted to 3). After the incubation, thegel remained red, which indicated retention of significant amounts ofdoxorubicine. Analogous experiments with gels heated for 8 hours(Example 3) showed no doxorubicine retention.

EXAMPLE 6 Polyalcohol-DTPA Derivative

Dry polyalcohol (Example 2), 50 milligrams, was dissolved in 0.2 mL DMSOand mixed with a solution of 2 milligrams of (DTPA)diethylenetriaminepentaacetic acid cycloanhydride in 0.05 mL DMSO. Tenmicroliters of triethylamine was added, and the reaction mixture wasincubated for 1 hour. The resultant mixture was diluted with water (1mL) and the polymer was separated by gel chromatography (Sephadex G25/water) and lyophilized to yield 46 milligrams.

EXAMPLE 7 Graft Copolymer of Polyalcohol and Poly-L-lysine-DTPA

A graft copolymer was produced via DTPA-labeled poly-L-lysineconjunction with aldehyde polymer followed by borohydride reduction. Twomilligrams of poly-L-lysine (40 kDa hydrobromide, 85% modified with DTPAand labeled with Rhodamin X, 0.5% modification) was dissolved in 1 mL ofwater and mixed with 5 mL of 4.5% polyaldehyde solution (Example 1).After 10 minutes of incubation, 0.1 mL of 10 milligrams/mL sodiumcyanoborohydride solution were added. One hour later, the reactionmixture was mixed with 1 mL of 50 milligrams/mL sodium borohydride.After 1 hour of incubation, the pH was adjusted to 6 and high molecularweight compounds were separated by gel-filtration (Sephadex G 25/water).The polymer fraction was separated into two fractions by diafiltrationusing Amicon™ YM-100 membrane. Rhodamin label and DTPA were found onlyin the high molecular fraction, indicating copolymer formation.

EXAMPLE 8 Iron Oxide Colloid Stabilized by Polyalcohol

A dextran-stabilized iron oxide colloid (particle size 22±3 nm) wasprepared as previously described (Papisov et al., J. Magnetism and Mag.Mater. 122 (1993), 383). A colloid solution in 10 mL of water (0.5milligrams/mL by iron) was mixed with 1 gram dry sodium periodate andincubated for 1 hour at 25° C. Sodium borohydride, 1.47 g in 5 ml waterwas added, and the reaction mixture was incubated for 1 hr. Then pH wasadjusted to 6.5. Twenty min. later, the colloid was precipitated withethanol and resuspended in 10 ml water (3 tines). Ethanol was removed byvacuum evaporation and the colloid was dialysed against 0.9% NaCl. Theresultant preparation was stable; particle size was practicallyunchanged (21±4 nm).

EXAMPLE 9 Biokinetics of ¹¹¹ In Labeled Polyalcohol-DPTA Derivatives

Polyalcohol-DPTA derivative (example 6), 5 milligram was dissolved in 1mL 0.2 M sodium citrate buffer (pH=5.5) and mixed with a solution of ¹¹¹InCl, 52 μCi. After a 5 minute incubation period, the In-labeled polymerwas separated by gel chromatography (Sephadex G 25/0.9% NaCl) to yield49 μCi in 2 mL of eluate.

Radiolabelled polymer was injected intravenously in two Sprague-DawleyCD rats (male, 200 and 300 g), 1.5 mg (15 μCi) in each. Observation ofradiolabel kinetics by dynamic scintigraphy demonstrated polymercirculation without accumulation in the reticuloendothelial system (andother tissues) with blood half-life ca. 2 hours. Study of radiolabeldistribution 20 hours after injection confirmed low tissue uptake, ascan be seen in FIG. 2.

EXAMPLE 10 Crosslinked Polyaldehyde Gel

Polyaldehyde polymer (Example 1), 100 mg, was dissolved in 0.5 ml water.Ethylenediamide dihydrochloride, 5 mg, and sodium cyanobohydride, 5 mg,were dissolved in 0.02 ml water. Solutions were mixed. After 3 hrincubation, the resultant gel was washed with water and dried withethanol.

EXAMPLE 11 Polyacid of Polyaldehyde

Polyaldehyde polymer (Example 1), 20 mg, was dissolved in 1 ml waterand, mixed with 5 ml 0.1 M iodine solution in 0.1 M KI. 1 ml of 1 M NaOHwas added by 5 μl aliquots. After 1 hr incubation, polymer was separatedusing membrane filter with 10 kDa cutoff, purified by gel chromatography(Sephadex G-25/water) and lyophilized.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

What is claimed is:
 1. An interface component comprising a biodegradablebiocompatible polyacetal, said biodegradable biocompatible polyacetalincluding a compound having a chemical structure of: ##STR9## wherein R¹is a biocompatible group and includes a carbon atom covalently attachedto C¹, R^(x) includes a carbon atom covalently attached to C², n is aninteger, and wherein R², R³, R⁴ and R⁵ are biocompatible groups and areselected from the group consisting of hydrogen and organic moieties, andfurther provided that at least one of R¹, R², R³, R⁴ and R⁵ ishydrophilic.
 2. A composition comprising the interface component ofclaim 1 and a macromolecule attached to the interface component.
 3. Acomposition comprising the interface component of claim 1 and a micelleattached to the interface component.
 4. A composition comprising theinterface component of claim 1 and a liposome attached to the interfacecomponent.
 5. A composition comprising the interface component of claim1 and a surface attached to the interface component.
 6. A biomedicalpreparation comprising a biodegradable biocompatible polyacetal, saidbiodegradable biocompatible polyacetal including a compound having achemical structure of: ##STR10## wherein R¹ is a biocompatible group andincludes a carbon atom covalently attached to C¹, R^(x) includes acarbon atom covalently attached to C², n is an integer, and wherein R²,R³, R⁴ and R⁵ are biocompatible groups and are selected from the groupconsisting of hydrogen and organic moieties, and further provided thatat least one of R¹, R², R³, R⁴ and R⁵ is hydrophilic.
 7. The biomedicalpreparation of claim 6 wherein the biomedical preparation is a fiber. 8.The biomedical preparation of claim 6 wherein the biomedical preparationis a gel.
 9. The biomedical preparation of claim 6 wherein thebiomedical preparation is a solution.